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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 2 825-834
Copyright © 2002 by The Endocrine Society

Other Original Articles

Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men

A. Gentili, T. Mulligan, M. Godschalk, J. Clore, J. Patrie, A. Iranmanesh and J. D. Veldhuis

Department of Internal Medicine (J.C.), General Clinical Research Center, Virginia Commonwealth University, Medical College of Virginia, Geriatrics and Extended Care Service Line, Richmond, Virginia 23298; Geriatrics and Extended Care Service (A.G., T.M., M.G.), McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; Division of Endocrinology (J.P., J.D.V.), Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202; and Endocrine Section (A.I.), Medical Service, Salem Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: J. D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu

Abstract

The present clinical study compares the impact of low- and high-dose parenteral testosterone (T) supplementation on daily GH secretory patterns and serum IGF-I, IGFBP-1, and IGFBP-3 concentrations in healthy older (60–82 yr) and young (20–40 yr) men. To this end, we administered three consecutive weekly injections of randomly ordered saline and either a low (100 mg) or a high (200 mg) dose of testosterone enanthate im; namely, saline (n = 17, young and n = 16, older), a low dose (n = 8 young, n = 8 older) and a high dose (n = 9 young, and n = 8 older) of androgen. To monitor somatotropic-axis responses, blood was sampled every 10 min for 24 h for later chemiluminescence-based assay of serum GH, RIA of serum IGF-I, and immunoradiometric assay of serum IGFBP-1 and IGFBP-3 concentrations. Data were analyzed via a nested analysis of covariance statistical design. At baseline (saline injection), older, compared with young, men maintained: 1) similar serum total T, IGFBP-1, and IGFBP-3 but reduced IGF-I concentrations, namely, mean (±SEM) IGF-I 160 plus or minus 15 vs. 280 plus or minus 18 µg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 ± 0.09 vs. 1.2 ± 0.20 µg/liter, P = 0.031); 3) more disorderly GH release patterns (approximate entropy 0.501 ± 0.058 vs. 0.288 ± 0.021, P < 0.001); and 4) blunted 24-h rhythmic GH output (nyctohemeral amplitude 0.25 ± 0.05 vs. 0.47 ± 0.08 µg/liter, P = 0.025). Serum T concentrations (ng/dl) did not differ in the two age groups supplemented with either a low dose [550 ± 50 (young) and 544 ± 128 (older)] and high [1320 ± 92 (young) and 1570 ± 140 (older)] dose of T. The 100-mg dose of androgen exerted no detectable effect on GH secretion in either age cohort but increased the serum IGF-I concentration in young men by 20% (P = 0.00098). The 200-mg dose of T failed to alter daily GH production in young volunteers but in older men stimulated: 1) a 2.03-fold rise in the mean (24-h) serum GH concentration (P = 0.0053, compared with the response to saline); 2) a 1.20-fold increase in basal (nonpulsatile) GH production (P = 0.039); 3) a 2.15-fold amplification of GH secretory burst mass (P = 0.0020); 4) a 2.17-fold elevation of the Mesor of nyctohemeral GH output (P = 0.025); 5) a 1.79-fold enhancement in GH approximate entropy (P = 0.0003); and 6) a 40% increase in the fasting serum IGF-I concentration (P = 0.000005). Multivariate statistical analysis indicated that following high-dose T administration, the E2 increment significantly predicted the IGF-I increment in both age groups combined (P = 0.003); T dose positively forecast the serum total IGF-I concentration (P = 0.0031); and age and T dose jointly determined serum LH concentrations (P = 0.031). In summary, neither a physiological nor a pharmacological dose of T administered parenterally for 3 wk augments daily GH secretion in eugonadal young men. In contrast, a high dose of aromatizable androgen significantly amplifies 24-h basal, pulsatile, entropic, and nyctohemerally rhythmic GH production and elevates the serum IGF-I concentration in older men. The mechanistic basis for the foregoing age-related distinction in GH/IGF-I axis responsivity to T is not known.

CROSS-SECTIONAL CLINICAL INVESTIGATIONS in pubertal boys and aging men have identified a positive correlation between the serum total, free or bioavailable testosterone (T) concentration and the daily GH secretion rate and/or the serum IGF-I concentration (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). Interventional analyses further indicate that short-term T administration consistently stimulates GH and IGF-I production in androgen-deficient individuals (13). Although we are unaware of any direct age comparisons, in several studies eugonadal (T-replete) young men showed little or no somatotropic response to T supplementation (13, 14, 15, 16, 17, 18).

Little is known about the impact of T repletion on the GH/IGF-I axis in older men. This issue has relevance clinically, inasmuch as the systemic availabilities of T and GH/IGF-I decline in parallel in the aging male (3, 4, 5, 6, 19, 20, 21, 22). Accordingly, the present study compares the impact of graded (two-dose) T supplementation on GH dynamics and serum concentrations of IGF-I, IGFBP-1, and IGFBP-3 in older and young men.

Materials and Methods

Clinical protocol

The study was approved by the University of Virginia Health Sciences Center Human Investigation Committee, Virginia Commonwealth University Committee on the Conduct of Human Research, and Veterans Affairs Medical Center Research and Development Committee. We studied a total of 33 healthy male volunteers, namely 17 young (age 20–40 yr) and 16 older (age 60–82 yr) men. Health was affirmed by detailed medical history, physical examination, and screening blood tests of hepatic, renal, metabolic, hematological, and endocrine function (2, 3, 15, 18). Exclusion criteria included the use of prescription medications; drug, alcohol, narcotic, or cigarette abuse; acute or chronic organic or psychiatric illness; recent transmeridian travel (more than three time zones within the preceding 10 d) and/or any acute weight change (>2 kg in 3 wk). Each subject provided written informed consent and was paid for participation in the study.

The design was a prospectively randomized, double-blind, placebo-(saline) controlled, nested intervention, wherein each volunteer received saline and either a low or high dose of T. Eight young and eight older subjects received 0.5 cc saline and testosterone enanthate 100 mg im weekly for 3 consecutive wk. This dose was intended to produce young-adult serum total T concentrations (23). Nine other young and eight older subjects received 0.5 cc saline and testosterone enanthate 200 mg im weekly for 3 wk to impose a supraphysiological androgen stimulus. Sampling for GH/IGF-I was conducted 3–5 d after the third injection of saline or T.

Volunteers were admitted to the General Clinical Research Center (GCRC) on the evening before blood sampling. Subjects received a standardized weight-maintaining diet of 55% carbohydrate, 30% fat, and 15% protein in meals served at 0800, 1200, and 1700 h. Lights were put out at 2300 h. After overnight adaptation to the GCRC, an indwelling catheter was placed in a forearm vein to collect blood samples every 10 min for 24 h (0800 to 0800 h). Volunteers were allowed to ambulate to the lavatory but were not permitted to sleep during the daytime or exercise vigorously. A minimum washout interval of 4 wk was imposed between the saline and T interventions.

Assays

Blood samples were allowed to clot at room temperature. Sera were separated and stored at -20 C. Serum GH concentrations were assayed in duplicate in each sample using a chemiluminescence-based assay with a sensitivity of 0.005 µg/liter (3 SD above the zero-dose tube) and an intraassay precision (coefficient of variation) of 4.6–8.5% for the concentration range measured here (4, 5, 6). All sera in a given subject (n = 289 samples) were assayed together. Serum total T, E2, SHBG, IGF-I, IGFBP-1, IGFBP-3, FSH, and LH concentrations were measured by RIA (T), chemiluminescence (E2), or immunoradiometric assay. The remainder in a single pool of serum prepared from all 145 samples collected on a given admission, as described earlier (2, 3, 4, 5, 6, 7, 15, 24, 25).

Deconvolution analysis

Multiparameter deconvolution analysis was used to quantitate the basal (nonpulsatile) GH secretion rate; the number and mass of significant GH secretory bursts; the endogenous GH half-life; and thereby total daily GH secretion (4, 5, 6). Ninety-five percent statistical confidence intervals (CIs) for GH pulse mass were determined by the Monte Carlo support-plane procedure (26, 27, 28, 29).

Nyctohemeral (24-h) rhythmicity of GH release

Twenty-four-hour rhythms of serum GH concentrations were evaluated by regression of a simple cosine function of 1440-min periodicity on each time series (30, 31). We calculated the amplitude (half the difference between the zenith and nadir), acrophase (time of maximal value within the 24-h rhythm), and mesor (mean value about which the cosine rhythm varied).

Approximate entropy (ApEn)

ApEn is a model-independent regularity statistic designed to quantify the regularity or orderliness of a time series (32, 33, 34, 35). ApEn is a single nonnegative number that monitors relative pattern consistency in serial data (32, 34, 36, 37). To compute ApEn, two input parameters are specified, m (pattern length) and r (de facto tolerance). In this study, we used m = 1 and r = 20% of the SD of the individual subject’s time series, as validated earlier (33, 34, 35, 38).

Statistical analyses

Baseline (placebo) data in young and older men were compared by the two-tailed Welch t test, which extends the t test to accommodate unequal variance. To assess within-subject interventional effects, we calculated as the ratio of the GH/IGF-I response to supplementation with T vs. saline. The logarithms were analyzed to equalize within-group residual variance. A primary analysis of covariance model was specified to include two classification variables: age (young, older) and T dose (low, higher) and a term to identify any age-by-dose interaction. Analyses were based on restricted maximum likelihood with a multiple comparison type I error rate of 0.05 using the least significant difference criterion. Data are presented as the geometric mean (±SEM) ratios of the response to T vs. saline. Linear regression analysis was used to relate the logarithm of incremental (treatment minus placebo) changes in serum concentrations T or E2 to the primary response variables. Statistical computations were carried out in SAS version 6.12 with the mixed model software of Proc Mixed (SAS version 6.12 SAS/STAT Software Changes and Enhancements, 1996; SAS Institute, Cary, NC).

Results

Twenty-four hour serum GH concentration profiles and corresponding deconvolution-calculated GH secretory rates are illustrated graphically for several subjects in Fig. 1Go. Serum total IGF-I concentrations (and responses to T) are summarized in Fig. 2AGo. Statistical analyses of saline-pretreated subjects (baseline data) revealed that older, compared with young, men exhibited: 1) a significantly lower mean (±SEM) 24-h serum GH concentration of 0.27 plus or minus 0.04 vs. 0.41 plus or minus 0.06 µg/liter (P = 0.024) (Fig. 2BGo); 2) a comparable mean (24-h pooled) serum total T concentration of 468 plus or minus 43 vs. 516 plus or minus 34 ng/dl (P = NS) but significantly lower mean T/SHBG ratio owing to a 2.3-fold higher mean SHBG level in older men (91 ± 8.1 vs. 40 ± 4.6 nmol/liter, P < 0.001) (Fig. 3Go); 3) a reduced global mean basal (saline-exposed subjects) serum total IGF-1 concentration of 160 plus or minus 15 vs. 280 plus or minus 18 µg/liter, (P < 0.001) (Fig. 2Go) but similar serum IGFBP-1 and IGFBP-3 concentrations (Table 1Go); 4) a lower mass of GH secreted per burst (0.68 ± 0.09 vs. 1.2 ± 0.20 µg/liter, P = 0.031) (Fig. 4Go); 5) higher GH ApEn, denoting more disorderly GH release (0.501 ± 0.058 vs. 0.288 ± 0.021, P < 0.001) (Fig. 5Go); and 6) a blunted mean 24-h rhythmic GH amplitude and mesor (Table 1Go).




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  		Figure 1. A, Illustrative individual profiles of serum GH concentrations obtained by sampling blood every 10 min for 24 h in healthy young and older men administered randomly ordered saline (placebo) vs. either a low dose (100 mg) or a higher dose (200 mg) of testosterone enanthate im weekly for three consecutive doses. B, Corresponding deconvolution-calculated GH secretory rates.

 


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  		Figure 2. Contrasts in serum GH (top) and total IGF-I (bottom) concentrations measured after three consecutive weekly injections of either a low or a high dose of testosterone enanthate (100 or 200 mg im), compared with saline, in randomly assigned order in young and older men. Data are the median, interquartile range, and extreme values (box-and-whisker plots). Numerical values are the mean ± SEM (see Results). Unshared (different) alphabetic superscripts identify significant mean contrasts.

 


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  		Figure 3. Serum total T concentrations (upper), SHBG concentrations (middle) and T/SHBG ratios (lower) in young and older men given saline and either a low (100 mg, n = 8 young, n = 8 older) or high (200 mg, n = 9 young, n = 8 older) dose of testosterone enanthate im weekly three times (see Materials and Methods). Data are the mean ± SEM. Means with different (unshared) alphabetic superscript differ significantly. To convert T concentrations to SI units (nmol/liter), multiply the indicated value by 0.0347.

 

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  		Table 1. Selected measures of GH dynamics and reproductive hormone concentrations in young and older men administered saline and either a low or high dose of T im for 3 wk

 


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  		Figure 4. Augmentation of the mass of GH secreted per burst (top) and stable GH interpulse-interval values (lower) in young and older men administered saline and either a low or high dose of testosterone enanthate (T) (100 or 200 mg im) weekly for 3 wk. Data are box-and-whisker plots, which highlight the median, interquartile, and absolute ranges. Unshared alphabetic superscripts denote significantly different means at the indicated overall P value.

 


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  		Figure 5. ApEn (1, 20%) quantitation of the relative orderliness (or regularity) of pulsatile GH release patterns in young and older men administered saline (control) and either a low or a high dose of T. Data are observed ApEn (top) or ApEn ratios (bottom), wherein higher values denote more disorderly GH secretory patterns. Data are the mean ± SEM.

 
In young men, administration of a low dose of T did not alter the mean serum total T concentration. A higher dose increased the latter value by 2.7-fold [95% CIs (2.14, 3.34), P < 0.001; Fig. 3Go]. In older men, the serum total T concentration increased by (geometric mean) 1.3-fold [(1.03, 1.65), P = 0.027] after the low-dose and by 3.5-fold [(3.4, 4.47), P < 0.001] after the high-dose intervention. T repletion was biologically effectual in older men because serum SHBG concentrations declined in the elderly cohort (Fig. 3Go). Serum T/SHGB ratios were thus lower in older subjects at all time points examined. Serum LH and FSH concentrations fell by several-fold in response to both T doses in all subjects (P < 10-3; Fig. 6Go and Table 1Go). By multivariate analysis, age and T dose jointly determined the degree of decline in serum LH (but not FSH) concentrations (P = 0.031). In particular, older men exhibited greater LH suppression during low-dose, and lesser LH suppression during high-dose, androgen repletion than young individuals. E2 concentrations did not change significantly in either age cohort administered the low dose of T (Table 1Go) but rose following the high dose by 1.5-fold [(1.15, 1.98), P = 0.004] in young men and by 2.8-fold [(2.08, 3.75), P < 0.0001] in older men (Fig. 3Go).



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  		Figure 6. Suppression of mean (24-h pooled) serum LH and FSH concentrations by either a low or high dose of T administered im for 3 wk, compared with saline, in young and older men. Values are within-subject percentage (%) basal (saline) 24-h pooled serum gonadotropin concentrations. Percentage suppression would represent 100% minus the indicated value. Asterisks denote significant age contrast. Data are the mean ± SEM.

 
Nested analysis of covariance revealed that T dose influenced mean serum concentrations of IGF-I (P = 0.0031) and IGFBP-3 (P = 0.049) but not IGFBP-1 (P = NS) (Table 1Go and Fig. 2Go). In addition, age and T dose jointly predicted the serum total IGF-I concentration (P = 0.007). In young men, IGF-I increased by 1.21-fold [(1.05–1.34), P = 0.0098] and 1.22-fold [(1.07, 1.35), P = 0.0027], respectively, during low- and high-dose T supplementation. In older men, IGF-I did not change after the low dose but increased by 1.4-fold [(1.22, 1.54), P < 0.0001] following the high dose of androgen. Deconvolution analysis was applied to quantitate specific measures of GH secretion after saline vs. T injection. Neither dose of androgen altered any measure of daily GH production in young subjects. The low dose of T was also ineffectual in older individuals. In contrast, in aging men, compared with saline, injection of the high dose of T relative to placebo injections stimulated a 2.03-fold [(1.26, 3.27), P = 0.005] increase in the mean serum GH concentration (Fig. 2BGo); a 2.15-fold augmentation [(1.36, 3.41), P = 0.002] of GH secretory burst mass (Fig. 4Go); and a 1.10-fold increase [95% CI (1.02, 2.30), P = 0.039] in daily basal/nonpulsatile, with a corresponding elevation in total daily GH secretion (Fig. 7Go). On the other hand, the GH interpulse interval and GH half-life were not altered by either intervention (Fig. 4Go and Table 1Go). Linear regression analysis revealed a significantly positive correlation between the (logarithmic) incremental changes in serum total E2 and IGF-I concentrations only following the high dose of T supplementation (Fig. 8Go).



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  		Figure 7. Pulsatile (top) and total daily (bottom) GH secretion in young and older men administered placebo and either a low or a high dose of T parenterally for 3 wk. Basal secretion is the difference between total daily and pulsatile GH production (see Results). Data are the mean ± SEM presented at described in the legend of Fig. 4Go.

 


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  		Figure 8. Positive linear relationship between the (logarithmic) incremental rise in serum total E2 and IGF-I concentrations following high-dose (200 mg) (bottom) but not low-dose (100 mg) (lower) T supplementation in the combined cohort of young (•) and older men ({circ}) (see Results).

 
The ApEn statistic was used to quantitate the regularity of GH release patterns (33, 34, 35, 39). Low-dose T administration had no effect on GH ApEn in either age group (Fig. 5Go). Injections of a high dose of T elevated GH ApEn only in older men, namely, by 1.79-fold [(1.34, 2.38), P = 0.0003], which signifies more irregular GH secretion.

Nyctohemeral GH release was appraised by cosinor analysis. A low dose of T paradoxically lowered the mesor and amplitude of 24-h rhythmic serum GH concentrations in older men (Table 1Go). However, the high dose of androgen elevated the GH mesor in older men by 2.17-fold [(1.10, 3.83), P = 0.025]. Neither intervention affected the acrophase of 24-h rhythmic GH release.

Discussion

The present clinical study demonstrates that administration of a pharmacological dose of T administered parenterally for 3 wk significantly stimulates basal (nonpulsatile) GH release, augments GH secretory burst mass, increases pulsatile and total 24-h GH production, heightens the disorderliness of GH profiles, amplifies nyctohemeral GH output, and elevates serum IGF-I concentrations significantly in healthy older (but not young) men. Serum IGFBP-1 and IGFBP-3 concentrations showed minimal alterations over this interval, whereas LH and FSH release was suppressed markedly. An identical T supplementation regimen failed to stimulate any measured end points of GH/IGF-I secretion in young men, except for increasing the serum IGF-I concentration slightly. The foregoing multiple responses of the GH-IGF-I axis in older men to a high dose of T resemble the consistent facilitation of basal, pulsatile, entropic, and 24-h rhythmic GH secretion and concomitant elevation of serum IGF-I concentrations observed in normal puberty and in hypogonadal boys replaced with T (7, 39, 40, 41, 42).

Supraphysiological T supplementation increased serum IGF-I concentrations in older men by 40% and in young men by 20%. Serum E2 concentrations rose concomitantly in both age groups and predicted the incremental changes in IGF-I (Fig. 8Go). T also stimulates combined GH and IGF-I production in prepubertal children, hypogonadal middle-aged men, and transsexual women (8, 13, 15, 39, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56). However, estrogen and nonaromatizable androgens typically fail to elevate systemic IGF-I concentrations in the human (13, 15, 39, 56, 57, 58) (Fig. 9Go). Thus, why incremental serum E2 concentrations in young and older men given T injections correlate positively with incremental IGF-I production is not clear. One consideration is that other selected in situ estrogenic or androgenic metabolites of T mediate augmented GH and IGF-I output in this setting (14, 48, 59, 60, 61, 62). Although only a single type of AR is known, certain androgenic metabolites appear to exert tissue-preferential effects (23, 63). In addition, recent studies in transgenic mice harboring homologous disruption of the {alpha} or ß estrogen receptor gene point to a role for the former in mediating GH IGF-I generation (64). Moreover, in the adult male rat, the {alpha} (rather than ß) E2 receptor subtype is expressed in 70% of hypothalamic GHRH neurons (65). These observations allow for, but do not prove, possible selective control of the GH-IGF-I axis via E2 receptor subtype-specific mechanisms.



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  		Figure 9. Schema of primary actions of T on GH, IGF-I, and IGFBP-1 and IGFBP-3 inferred in the present study in older men, compared with earlier reports of estrogen action (8 38 39 50 55 66 67 71 ).

 
T supplementation in a high dose stimulated both basal and pulsatile (and, hence, total daily) GH secretion in older men. The clinical mechanisms that control basal GH release are not well established. Limited human investigations indicate that, whereas estrogen does not alter, somatostatin and octreotide can repress and GHRH and GHRP-2 can stimulate basal GH production (5, 6, 66, 67, 68). Such findings suggest that a high dose of T may suppress hypothalamic somatostatin secretion and/or enhance GHRH/GHRP release in older men (Fig. 8Go). Why young men do not respond analogously is not known.

Short-term administration of a high dose of T increased GH ApEn in older men only. This outcome denotes the induction of less orderly GH secretory patterns (35). Comparable changes in GH secretory regularity occur following supplementation with an aromatizable androgen or estrogen in children and/or postmenopausal women (39, 39, 41) and emerge transiently in normal midpuberty in boys (34, 38, 39, 40, 41, 55, 69). From a mathematical perspective, more disorderly GH output indicates altered within-axis feed-forward and/or feedback control (32, 33, 34, 35). In this regard, fixed infusions of GHRP-2 or GHRH likewise drive greater irregularity (elevated GH ApEn) of 24-h serum GH concentration profiles (5, 41, 66, 67, 70). Conversely, injections of somatostatin or IGF-I enforce more orderly patterns of GH secretion (lower GH ApEn) (70, 71). By inference, therefore, T may raise GH ApEn in older men by facilitating endogenous secretagogue action and/or by muting negative-feedback signaling within the GH-IGF-I axis.

The low (midphysiological) dose of T used here increased the mean serum total T concentration by 30% and tended to lower SHBG concentrations in older (but not young) men. These age distinctions may reflect the elevated baseline serum SHBG concentration in older subjects, which can retard the metabolic clearance of T (23). The low dose of androgen also doubled the mesor of 24-h rhythmic GH release in elderly, but not young, adults. Nyctohemeral GH secretion is governed conjointly by nutrient intake, the sleep-wake activity cycle, circadian inputs and hypothalamic GHRH, GHRP, and/or somatostatinergic signals (8, 72, 73, 74). Non-GHRH and non-GHRP signals may be relevant because ectopic tumoral secretion of GHRH or sustained iv infusion of GHRH and/or GHRP-2 increases, whereas loss-of-function mutation of the human GHRH receptor markedly diminishes 24-h rhythmic GH secretion (5, 66, 67, 75).

Maintenance of serum total T concentrations within the young-adult male range for 3 wk in older men elevated 24-h rhythmic GH release but did not stimulate basal, pulsatile, or entropic measures of daily GH secretion or normalize serum IGF-I concentrations. Such observations contradict the a priori hypothesis that relative hyposomatotropism in older men is owing solely to an age-related decline in systemic T availability, at least over the short term. Whether more prolonged and/or more physiological androgen supplementation would be more effectual in older men is not known. Indeed, the precise threshold and/or dose dependency of T’s stimulation of GH and IGF-I output in older men remains to be established.

Short-term replacement of T in physiological amounts stimulates the GH-IGF-I axis in prepubertal boys and middle-aged hypogonadal men (8, 13, 39, 41, 58). In contrast, eugonadal young men fail to respond analogously. Thus, we speculate that responsiveness of the GH-IGF-I axis to androgen repletion may be conditional on androgen dose, age, and/or degree of T deficiency (23, 76).

From a multivariate statistical perspective, age and T dose jointly determined the degree of suppression of mean (24-h) serum LH but not FSH concentrations. Whereas both doses of T inhibited LH release significantly in young and older men, the low does was more and the high dose less effectual in older individuals. The basis for this age-related contrast is not clear but could reflect randomization or selection bias and/or the relatively small size of the study groups. However, other clinical investigations have reported variously normal, blunted, or accentuated androgenic negative feedback on LH secretion in the older male (23, 77, 78, 79, 80, 81, 82, 83). In addition, assuming that the observed decrease in serum SHBG concentrations mirrors the in vivo biological action of androgen, then the greater decline in SHBG observed here in older men exposed to T would point to heightened responsiveness of this hepatic glycoprotein to androgen action (23). Accordingly, further studies of the potency and efficacy of androgen action on selected target tissues will be required to clarify whether and how aging alters the tissue-specific effects of T and/or its principal metabolites.

In summary, parenteral administration of a high dose of T for 3 wk in healthy older men stimulates basal, pulsatile, and total daily GH secretion; heightens the irregularity (ApEn) of GH release patterns; enhances 24-h rhythmic GH production; normalizes serum IGF-I concentrations; and reduces serum LH, FSH, and SHBG concentrations. Serum IGFBP-1 and IGFBP-3 levels do not change remarkably. Young men treated in the same manner show suppression of LH and FSH release but only a small rise in serum IGF-I concentrations and no detectable amplification of GH secretion. The precise neuroendocrine mechanism(s) subserving these age-related contrasts and the threshold amount of T required to elicit such distinctions are not known.

Acknowledgments

We thank Margaret T. Kidd for excellent editorial assistance; Paula P. Azimi for the deconvolution analysis, data management, and graphics; Brenda Grisso for performance of the immunoassays; the nursing staff at the University of Virginia and Virginia Commonwealth University General Clinical Research Centers for conducting the research protocols. This focused report necessarily omits many primary references because of editorial constraints.

Footnotes

This work was supported in part by the General Clinical Research Centers of the University of Virginia and Medical College of Virginia, a VA Merit Review grant, and NIH Grant RO1-AG-19695.

Abbreviations: ApEn, Approximate entropy; CI, confidence interval.

Received June 22, 2001.

Accepted October 29, 2001.

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